Identification of genetic factors responsible for the pathogenesis of essential hypertension

原发性高血压是心血管疾病的主要危险因素，其病因尚不清楚。虽然基因与环境的相互作用在原发性高血压的发病机制中起重要作用，但这种相互作用的确切机制尚未阐明。为了证明全基因组扫描的可行性，我们向日本千年基因组计划高血压任务小组提供了大量的人类DNA样本（约1万至10万份），结果发现了几个新的候选基因。利用候选基因方法，我们开展了Handai研究和几项大型遗传流行病学研究（S， O， A， TS），结果我们还发现了一些基因-环境相互作用。首先，通过对日本人AGT、ADD1、GNB3、CYP11B2基因多态性等位基因频率的比较，指出日本人盐敏感等位基因频率高于白种人。噻嗪类药物敏感的NaCl共转运体基因的遗传多态性（突变被认为是Gitelman综合征的遗传原因）也仅与女性原发性高血压的患病率有关。此外，MTHFR多态性增加了吸烟女性颈动脉粥样硬化的风险，adrb2和ET1基因多态性与肥胖原发性高血压的高患病率显著相关。结果提示，根据基因多态性的差异，个性化用药或改变生活方式的重要性。

Essential hypertension is major risk for cardiovascular disease and its cause is still unknown. Though the gene environmental interaction is important in the pathogenesis of essential hypertension, the precise mechanism of the interaction has not been elucidated yet. To demonstrate the whole genome scan, we provided a lot of number of human DNA samples (n>10,000) to Hypertension Task Force of Japanese Millennium Genome Project, resulted that several new candidate genes were identified. Using the candidate gene approach, we carried out Handai Study and several large genetic epidemiological studies (S, O, A, TS), resulted that we also revealed several gene-environmental interactions. First of all, we pointed out the high frequency of salt sensitive alleles in Japanese than Caucasians according to the comparison in the allele frequency of AGT, ADD1, GNB3, CYP11B2 gene polymorphisms. A genetic polymorphism of thiazide sensitive NaCl cotransporter gene, in which mutation was denoted as the genetic cause of Gitelman's syndrome, was also associated with the prevalence of essential hypertension only in females. In addition, MTHFR polymorphism increased the risk for carotid atherosclerosis in the females with smoking habit, and ADRB2and ET1 gene polymorphisms were significantly associated with high prevalence of essential hypertension with obesity. The obtained results suggested the importance of personalized medication or life style modification according to the difference of their gene polymorphism.